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t(2;9)(q12;q34) RANBP2/ABL1

Written2015-12Marc De Braekeleer, Nadia Guéganic, Alexandra Schifferli, Joëlle Tchinda.
Cytogenetics Laboratory, Faculty of Medicine, University of Brest, France marc.debraekeleer@univ-brest.fr (MdeB, NG)) Department of Hematology/Oncology, University Children's Hospital Basel, Switzerland (AS) University Children's Hospital Zurich, Switzerland (JT).

Abstract Review on t(2;9)(q12;q34), with data on clinics, and the genes involved.

Keywords chromosome 2; chromosome 9; RANBP2; ABL1

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS
ICD-Morpho 9811/3 B lymphoblastic leukaemia/lymphoma, NOS
Atlas_Id 1305
 
  GTG banding showing chromosomes 2 and 9 and the derivatives der(2) and der(9).

Clinics and Pathology

Disease Pre-B acute lymphoblastic leukemia
Epidemiology Two cases reported: a 15year-old male (Roberts et al., 2012; Roberts et al., 2014) and a 21-month girl (Braekeleer et al., 2015).
Evolution Alive 23 months after diagnosis in complete remission for one case, unknown for the other.

Cytogenetics

Note The t(2;9)(q12;q34)involves the RANBP2 and ABL1 genes. This fusion was first identified by RNA-sequencing in a boy with B-cell ALL (Roberts et al., 2012).
Cytogenetics Morphological t(2;9)(q12;q34) is identified by banding cytogenetics.
Cytogenetics Molecular FISH with a BCR-ABL probe showed 3 ABL signals. To determine the position of the breakpoints on chromosome 2, BACs located in bands 2q12.1 to 2q14.2 were used as probes in FISH experiments. A split signal on der(2) and der(9) was found with RP11-622D1, RP11-347H10, RP11-259O12, RP11-348G16 and RP11-953L12. These BAC clones overlap the RANBP2 gene and allow refinement of the breakpoint to a 25kb region covering the 5' end and the first three exons of RANBP2 (figure BAC).
 
  FISH with BACs RP11-953L12 (spectrum green, located in 2q12 and containing RANBP2) and RP11-83J21 (spectrum orange, located in 9q34 and containing the 3' part of ABL1) and CEP9 (in aqua) showing one fusion signal on der(2). No fusion is detected on der(9) because RP11-83J21 does not cover the 5' part of ABL1.

Genes involved and Proteins

Gene NameRANBP2 (RAN binding protein 2)
Location 2q12.3
Dna / Rna The RANBP2 (alias NUP358) gene contains 31 exons, spanning 66 kb. One major transcript with several alternative splicing variants is known.
Protein The protein has 3324 amino acids and is the largest component of nuclear pore complexes. It contains an N-terminal leucine-rich region, four RAN binding domains, eight zinc-finger motifs, a SUMO E3 ligase region and a C-terminal cyclophilin A-like domain. A detailed assessment of its functions is available elsewhere in the Atlas (Di Cesare E, Lavia P. RANBP2 (RAN binding protein 2. http://AtlasGeneticsOncology.org/Genes/RANBP2ID483.html).
Gene NameABL1 (v-abl Abelson murine leukemia viral oncogene homolog 1)
Location 9q34.12
Dna / Rna The ABL1 gene, spanning a 230kb region at band 9q34, includes the 5' alternative first exons 1b and 1a and ten common exons numbered from 2 to 11. Alternative splicing using exons 1b and 1a gives rise to mRNA of 7 and 6 kb, respectively.
Protein The ABL1 protein has three SRC homology (SH) domains called SH1, SH2 and SH3, of which SH1 that has tyrosine kinase function. The SH2 and SH3 domains are involved in protein-protein interactions, which regulate the tyrosine kinase activity; they are necessary for signal transduction function. The ABL1 protein has also three nuclear localization signal domains and three DNA binding regions and an F-actin binding domain.

Result of the chromosomal anomaly

Hybrid gene
Description The 3' region of ABL1 is translocated on the 5' region of RANBP2 on the der(2) and the 3' region of RANBP2 is translocated on the 5' region of ABL1 on der(9).
Detection FISH detection.
  
Fusion Protein
Description The fusion protein retains the leucine-rich domain, including a leucine zipper, located at the N-terminal of RANBP2 and the tyrosine kinase domain of the ABL1 protein.
Oncogenesis The leucine-rich region of RANBP2 is predicted to mediate homo-oligomerization of the fusion protein, leading to the activation of the tyrosine kinase of ABL1.
  

To be noted

Two other genes are known to fuse to RANBP2 and generate in-frame transcripts. These are ALK in inflammatory myofibroblastic tumor (Li et al., 2013;Ma et al., 2003), diffuse large B-cell lymphoma (Lee et al., 2014) and myeloid neoplasm (Lim et al., 2014;Maesako et al., 2014;Rottgers et al., 2010) and FGFR1 in myeloproliferative neoplasm (Gervais et al., 2013). In all cases, the fusion protein includes the leucine zipper portion of RANBP2 and the tyrosine kinase domain of the partner protein, leading to its activation.
Additional cases are needed to delineate the epidemiology of this rare entity:
you are welcome to submit a paper to our new Case Report section.
Case Report A pediatric case of acute lymphoblastic leukemia with t(2;9)(q12;q34) RANBP2-ABL1 fusion

Bibliography

A pediatric case of acute lymphoblastic leukemia with t(2;9)(q12;q34) RANBP2-ABL1 fusion
Braekeleer M de, Guéganic N, Schifferli A, Tchinda J.
Atlas Genet Oncol Haematol (in press)
 
A translocation t(2;8)(q12;p11) fuses FGFR1 to a novel partner gene, RANBP2/NUP358, in a myeloproliferative/myelodysplastic neoplasm
Gervais C, Dano L, Perrusson N, Hélias C, Jeandidier E, Galoisy AC, Ittel A, Herbrecht R, Bilger K, Mauvieux L
Leukemia 2013 Apr;27(5):1186-8
PMID 23041776
 
Identification of RANBP2-ALK fusion in ALK positive diffuse large B-cell lymphoma
Lee SE, Kang SY, Takeuchi K, Ko YH
Hematol Oncol 2014 Dec;32(4):221-4
PMID 24470379
 
Inflammatory myofibroblastic tumor with RANBP2 and ALK gene rearrangement: a report of two cases and literature review
Li J, Yin WH, Takeuchi K, Guan H, Huang YH, Chan JK
Diagn Pathol 2013 Sep 13;8:147
PMID 24034896
 
RANBP2-ALK fusion combined with monosomy 7 in acute myelomonocytic leukemia
Lim JH, Jang S, Park CJ, Cho YU, Lee JH, Lee KH, Lee JO, Shin JY, Kim JI, Huh J, Seo EJ
Cancer Genet 2014 Jan-Feb;207(1-2):40-5
PMID 24613277
 
Fusion of ALK to the Ran-binding protein 2 (RANBP2) gene in inflammatory myofibroblastic tumor
Ma Z, Hill DA, Collins MH, Morris SW, Sumegi J, Zhou M, Zuppan C, Bridge JA
Genes Chromosomes Cancer 2003 May;37(1):98-105
PMID 12661011
 
inv(2)(p23q13)/RAN-binding protein 2 (RANBP2)-ALK fusion gene in myeloid leukemia that developed in an elderly woman
Maesako Y, Izumi K, Okamori S, Takeoka K, Kishimori C, Okumura A, Honjo G, Akasaka T, Ohno H
Int J Hematol 2014 Feb;99(2):202-7
PMID 24307515
 
ALK fusion genes in children with atypical myeloproliferative leukemia
Röttgers S, Gombert M, Teigler-Schlegel A, Busch K, Gamerdinger U, Slany R, Harbott J, Borkhardt A
Leukemia 2010 Jun;24(6):1197-200
PMID 20428197
 
Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia
Roberts KG, Li Y, Payne-Turner D, Harvey RC, Yang YL, Pei D, McCastlain K, Ding L, Lu C, Song G, Ma J, Becksfort J, Rusch M, Chen SC, Easton J, Cheng J, Boggs K, Santiago-Morales N, Iacobucci I, Fulton RS, Wen J, Valentine M, Cheng C, Paugh SW, Devidas M, Chen IM, Reshmi S, Smith A, Hedlund E, Gupta P, Nagahawatte P, Wu G, Chen X, Yergeau D, Vadodaria B, Mulder H, Winick NJ, Larsen EC, Carroll WL, Heerema NA, Carroll AJ, Grayson G, Tasian SK, Moore AS, Keller F, Frei-Jones M, Whitlock JA, Raetz EA, White DL, Hughes TP, Guidry Auvil JM, Smith MA, Marcucci G, Bloomfield CD, Mrózek K, Kohlschmidt J, Stock W, Kornblau SM, Konopleva M, Paietta E, Pui CH, Jeha S, Relling MV, Evans WE, Gerhard DS, Gastier-Foster JM, Mardis E, Wilson RK, Loh ML, Downing JR, Hunger SP, Willman CL, Zhang J, Mullighan CG
N Engl J Med 2014 Sep 11;371(11):1005-15
PMID 25207766
 

Citation

This paper should be referenced as such :
Braekeleer M de, Guéganic N, Schifferli A, Tchinda J
t(2;9)(q12;q34) RANBP2/ABL1;
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Anomalies/t0209q12q34RANBP2-ABL1ID1305.html


Translocations implicated (Data extracted from papers in the Atlas)

 t(2;9)(q12;q34) RANBP2/ABL1

External links

RANBP2 (2q12.3) ABL1 (9q34.12)

RANBP2 (2q12.3) ABL1 (9q34.12)

Mitelman databaset(2;9)(q12;q34) [Case List]    t(2;9)(q12;q34) [Association List] Mitelman database (CGAP - NCBI)
arrayMapTopo ( C42) Morph ( 9811/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
 
Mitelman databaseRANBP2/ABL1 [MCList]  RANBP2 (2q12.3) ABL1 (9q34.12)
Mitelman databaseRANBP2/ABL1 [MCList]  RANBP2 (2q12.3) ABL1 (9q34.12)
 
Disease databaset(2;9)(q12;q34) RANBP2/ABL1
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed


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indexed on : Thu Nov 9 13:44:10 CET 2017


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